5X08

Crystal structure of broadly neutralizing anti-HIV-1 antibody 4E10, mutant Npro, with peptide bound

Summary for 5X08

• Entry DOI: 10.2210/pdb5x08/pdb
• Descriptor: Fab 4E10 Heavy chain, Fab 4E10 Light chain, Envelope glycoprotein gp160, ... (9 entities in total)
• Functional Keywords: broadly neutralizing antibody, mper, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 50375.73

Authors

Caaveiro, J.M.M.,Rujas, E.,Nieva, J.L.,Tsumoto, K. (deposition date: 2017-01-20, release date: 2017-04-05, Last modification date: 2024-10-23)

Primary citation

Rujas, E.,Insausti, S.,Garcia-Porras, M.,Sanchez-Eugenia, R.,Tsumoto, K.,Nieva, J.L.,Caaveiro, J.M.M.
Functional Contacts between MPER and the Anti-HIV-1 Broadly Neutralizing Antibody 4E10 Extend into the Core of the Membrane
J. Mol. Biol., 429:1213-1226, 2017

PubMed Abstract: The exceptional breadth of broadly neutralizing antibodies (bNAbs) against the membrane-proximal external region (MPER) of the transmembrane protein gp41 makes this class of antibodies an ideal model to design HIV vaccines. From a practical point of view, however, the preparation of vaccines eliciting bNAbs is still a major roadblock that limits their clinical application. Fresh mechanistic insights are necessary to develop more effective strategies. In particular, the function of the unusually long complementarity-determining region three of the heavy chain (CDRH3) of 4E10, an anti-MPER bNAb, is an open question that fascinates researchers in the field. Residues comprising the apex region are dispensable for engagement of the epitope in solution; still, their single mutation profoundly impairs the neutralization capabilities of the antibody. Since this region is very hydrophobic, it has been proposed that the apex is essential for anchoring the antibody to the viral membrane where MPER resides. Herein, we have critically examined this idea using structural, biophysical, biochemical, and cell-based approaches. Our results demonstrate that the apex region is not just a "greasy" spot merely increasing the affinity of the antibody for the membrane. We demonstrate the three-dimensional engagement of the apex region of the CDRH3 with the conglomerate of gp41 epitope and membrane lipids as a means of effective binding and neutralization of the virus. This mechanism of recognition suggests a standard route of antibody ontogeny. Therefore, we need to focus our efforts on recreating a more realistic MPER/lipid immunogen in order to generate more effective anti-HIV-1 vaccines.

PubMed: 28300601
DOI: 10.1016/j.jmb.2017.03.008

Experimental method

X-RAY DIFFRACTION (1.49 Å)